Acyl chlorides with alcohol

The reaction of acyl chlorides with alcohols is one of the best ways to synthesize an ester. 

The analogous reaction of acyl chlorides with alcohols is a highly effective way of producing esters. A base such as an alkali metal hydroxide, pyridine, or a tertiary amine is usually added to neutralize the HCl by-product. Because acyl chlorides are readily made from the corresponding carboxylic acids (Section 19-8), the sequence RCOOH RCOQ RCOOR is a good method for esterification. By maintaining neutral or basic conditions, this preparation avoids Ihe equilibrium problem of acid-catalyzed ester formation (Fischer estoification. Section 19-9). 

Esterification With Diazomethane Reaction of Acyl Chlorides With Alcohols Fischer Esterification... 

The traditional method for transforming carboxylic acids into reactive acylating agents capable of converting alcohols to esters or amines to amides is by formation of the acyl chloride. Molecules devoid of acid-sensitive functional groups can be converted to acyl chlorides with thionyl chloride or phosphorus pentachloride. When milder conditions are necessary, the reaction of the acid or its sodium salt with oxalyl chloride provides the acyl chloride. When a salt is used, the reaction solution remains essentially neutral. 

High yields (76-81%) of alcohols are also obtained by adding solutions of acyl chlorides in anhydrous dioxane or diethyl carbitol to a suspension of sodium borohydride in dioxane and brief heating of the mixtures on the steam bath [751], by stirring solutions of acyl chlorides in ether for 2-4 hours at room temperature with aluminum oxide (activity I) impregnated with a 50% aqueous solution of sodium borohydride (Alox) (yields 80-90%) [1014], by refluxing acyl chlorides with ether solutions of sodium trimethoxyborohydride [99], or by treatment of acyl chlorides in dichloromethane solutions with tetrabutylammonium borohydride at —78° [771]. A 94% yield of neopentyl alcohol was achieved by the reaction of trimethylacetyl chloride with tert-butylmagnesium chloride [324]. 

The preparation of tosylate and other sulfonate esters for use as leaving groups in nucleophilic substitution reactions (see Section 8.9) employs the reaction of a sulfonyl chloride (an acid chloride of a sulfonic acid) with an alcohol. Another example is shown in the following equation. Note the similarity of this reaction to the reaction of an acyl chloride with an alcohol to form an ester. 

The phosphorus-based nerve gases and insecticides act by deactivating acetylcholinesterase. Note that all of these compounds have a good leaving group on the phosphorus. They react readily with the nucleophilic hydroxy group of the enzyme to form a phosphate triester in a reaction that is very similar, both in its mechanism and its product, to the reaction of an acyl chloride with an alcohol to form an ester ... 

It s useful to be able to compare leaving group ability quantitatively. This is impossible to do exactly, but a good guide is pK. If we go back to the example of ester formation from acyl chloride plus alcohol, there s a choice of Me-, EtO-, and Cl-. The leaving group with the lowest p.fCaH is the best and so we can complete the reaction. 

A second, more versatile, method involves the O-acyl thiohydroxamates. These compounds are generally prepared by reaction of acyl chlorides with the commercial sodium salt (1) of 2-mercapto-pyridine A(-oxide (equation 6 X = Cl). Use of mixed anhydrides formed by reaction of the carboxylic acid with isobutyl chloroformate (equation 6 X = OCC>2CH2CHMe2) renders the procedure compatible with unprotected indoles, phenols, secondary and, presumably, tertiary alcohols. An alternative mode of preparation of the 0-acyl thlohydroxamates involves the s t (2) in reaction with the carboxylic acid (equation 7). 

This method is preferable in this case to the usual way of making esters—from acyl chloride plus alcohol—since steric hindrance makes that a very slow reaction with t-butanol. 

Often, the carboxylic acid groups are converted to acyl chlorides with SOCI2109 110 prior to esterification with various alcohols and reaction with other nucleophiles.111 Both mono- and difunctional ester-substituted bipyridines have been generated in moderate yield by palladium(O)-catalyzed carboalkoxylation of halo- or triflate-substituted precursors in the presence of CO, an alcohol, and a tertiary amine.112... 

The mixture was stirred at room temperature for 10 h and precipitated into 600mL of methanol. The copolymer was purified by two precipitations from THF into methanol. A similar procedure was used for reacting other acyl chlorides with poly(ACN-co-vinyl alcohol). ... 

Indeed this combination is an excellent reagent for preparation of acid chlorides and of alkyl chlorides. HMPT as solvent is useful also because it combines with the hydrochloric acid formed in many cases it is superior to pyridine. Reactions occur in good yield and at temperatures of about —20 to —10°. HMPT is also an excellent solvent for esterification of acyl chlorides with tertiary alcohols. 

Although excess amine is necessary in the reaction of an acyl chloride with an amine, explain why it is not necessary to use excess alcohol in the reaction of an acyl chloride with an alcohol. 

Regarding the S-acyl alkoxy chalcogenides [RC(0)E0R E=S, Se, Te], a few sulfur derivatives 123 RC(0)S0R have been prepared from acylsulfenyl chlorides with alcohols in the presence of pyridine [100,102]. The aromatic derivatives 123 (R=aryl) can also be obtained in good yields using aroylsulfenyl bromides with alcohols [189,253]. 

Pyridine is useful in promoting the formation of esters from acyl chlorides and alcohols it may function by reacting first with the acyl chloride to form a salt, which then acts as the acylating agent to the alcohol (Scheme 6.7). 

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